Construction of 18F-perfluorinated motifs by mechanistic leverage with fluorine

通过氟的机械作用构建 18F-全氟基序

• 批准号: EP/T031220/1
• 负责人: Matthew Tredwell
• 金额: $ 49.99万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FT031220%2F1
• 关键词: Construction; 18F; perfluorinated; motifs; mechanistic

The range of applications of fluorinated compounds is incredibly diverse, particularly when one considers the cyclotron-produced radioisotope fluorine-18, a radionuclide which decays by positron emission. Fluorine-18 has physical properties that are well-suited to the radiolabelling of small organic molecules for Positron Emission Tomography (PET) imaging, a medical imaging technique that is routinely used in academia and industrial laboratories to help answer key biomedical questions in the diagnosis of numerous diseases, as well as key applications in the drug development process. In fact PET imaging is unique in its ability to provide quantitative information on biological processes using radiolabelled compounds. This information is used in key decision making stages in the drug development pipeline by providing data on drug-target engagement, or determining the pharmacokinetic profiles. With the progression of "personalized medicine" to individually tailor diagnosis and treatment, PET imaging will play an increasingly important role in the future healthcare treatments. However, a crucial requirement of this medical imaging technique is the ability to synthesize the desired radioactive molecules necessary for imaging. In this regard, the synthesis of 18F-perfluorinated motifs is a major unmet challenge in the field of 18F-radiochemistry due the lack of suitable synthetic methods for their construction. This consequently limits the continued development of 18F-PET for diagnostic imaging and drug development.The main focus of this research is address a critical gap in 18F-radiochemical methodology, by providing methods to access the 18F-perfluorinated motifs typically found in pharmaceuticals and radiotracers. In doing so we will be able to expand the range and diversity of small molecules that can be radiolabelled with fluorine-18, and consequently further 18F-PET imaging as a healthcare technology. Key to this proposal is to fundamentally understand the chemical reactivity of the fluorinated precursors and their suitability for radiochemistry. It is well recognized that fluorinated compounds have remarkable properties and reactivity in comparison to their non-fluorinated counterparts, and studies have shown that fluorinated electrophiles are typically unreactive towards [18F]fluoride in bimolecular nucleophilic substitution reactions (SN2), the most common method to introduce [18F]fluoride.We propose to make use of the unique reactivity of fluorine atoms as leverage to help promote an alternative reaction pathway that is synergistic with the inherent reactivity of both the fluorinated precursor and [18F]fluoride. This will expand the 18F-radiochemical space such that researchers developing radiotracers for biomarkers or pharmaceuticals can consider entirely new functional groups and molecules to aid in their synthetic strategies. More generally we anticipate that the knowledge gleaned from this work on the reactivity of fluorinated building blocks will likely influence the construction of complex organofluorine compounds in research fields such as agrochemicals and materials science, where selective synthetic methods remain in high demand.

氟化化合物的应用范围非常多样，尤其是当人们考虑了回旋子产生的放射性同位素氟-18时，这是一种放射性核素，这种放射性核素会随正电子发射而衰减时。氟-18具有非常适合用于正电子发射断层扫描（PET）成像的小有机分子的放射性标记的物理特性，这是一种医学成像技术，通常用于学术界和工业实验室中，以帮助回答许多疾病诊断中的关键生物医学问题，以及在药物开发过程中的诊断。实际上，PET成像在使用放射性标记化合物提供有关生物过程的定量信息的能力方面是独一无二的。通过提供有关药物靶向参与的数据或确定药代动力学特征，这些信息用于药物开发管道中的关键决策阶段。随着“个性化医学”单独量身定制诊断和治疗的进展，宠物成像将在未来的医疗保健治疗中发挥越来越重要的作用。但是，这种医学成像技术的关键要求是能够合成成像所需的放射性分子。在这方面，由于缺乏适合其构建的合成方法，因此在18F-RadioChemistrion领域的合成是18F-RadioChemistion领域的一个主要挑战。因此，这限制了18F-PET的持续开发进行诊断成像和药物开发。这项研究的主要重点是通过提供访问通常在药物和射线镜药物中通常发现的18F普遍性基序的方法来解决18F-放射性化学方法论的关键差距。这样一来，我们将能够扩大可以用氟-18进行放射性标记的小分子的范围和多样性，从而将18F-PET成像作为医疗保健技术。该提案的关键是从根本上了解氟化前体的化学反应性及其对放射化学的适用性。众所周知，与非氟化的对应物相比，氟化化合物具有显着的特性和反应性，并且研究表明，氟化的亲电器通常对[18F]氟化物不反应[18f]在双肌分子核仁反应中的反应（SN2），这是对持续反应的最常见方法。有助于促进替代反应途径，该途径与氟化前体和[18F]氟化物的固有反应性协同作用。这将扩大18F降亚化学空间，以便为生物标志物或药物开发放射性示例的研究人员可以考虑全新的官能团和分子以帮助其合成策略。更普遍地，我们预计这项工作从氟化构件的反应性中收集的知识可能会影响研究领域中复杂的有机氟氨酸化合物（例如农业化学和材料科学）的构建，在这种研究领域中，选择性合成方法仍然很高。